ANTI MYCOBACTERIAL DRUGS

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ANTI MYCOBACTERIAL DRUGS

• Dr.Saeed Ahmad
• Department of Pharmacology
• King Saud University

• PHARMA TEAM !!

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Tuberculosis

• Tuberculosis is one of the worlds most
  widespread and deadly illnesses.
• Mycobacterium tuberculosis, the organism that
  causes tuberculosis infection and disease,
  infects an estimated 20 43 of the worlds
  population.
• 3 milion people worldwide die each year from the
  disease

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Tuberculosis

• Tuberculosis occurs disproportionately among
  disadvantaged populations such as the
  malnourished, homeless, and those living in
  overcrowded and sub standard housing.
• There is an increased occurance of tuberculosis
  among HIV ve individuals.

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Tuberculosis

• Infection with M tuberculosis begins when a
  susceptible person inhales airborne droplet
  nuclei containing viable organisms. Tubercle
  bacilli that reach the alveoli are ingested by
  alveolar macrophages. Infection follows if the
  inoculum escapes alveolar macrophage mirobicidal
  activity.

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Tuberculosis

• Once infection is established, lymphatic and
  hematogenous dissemination of tuberculosis
  typically occurs before the development of an
  effective immune response. This stage of
  infection, primary tuberculosis is usually
  clinically and radiologically silent.

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Tuberculosis

• In most persons with intact cell mediated
  immunty, T cells and macrophages surround the
  organisms in granulomas that limit their
  multiplication and spread. The infection is
  contained but not eradicated, since viable
  organisms may lie dormant within granulomas for
  years to decades.

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Tuberculosis

• Individuals with this latent tuberculosis
  infection do not have active disease and can not
  transmit the organism to others. However,
  reactivation of disease may occur if the hosts
  immune defenses are impaired.

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Tuberculosis

• Symptoms and Signs
• Malaise
• Anorexia
• Weight loss
• Fever
• Night sweats
• Chronic cough, blood with sputum
• Rarely, dyspnea

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Tuberculosis

• Investigations
• Chest radiograph shows pulmonary infilterates
  most often apical
• Positive tuberculin skin test reaction (most
  cases)
• Acid fast bacilli on smear of sputum or sputum
  culture positive for Mycobacterium tuberculosis

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Anti Mycobacterial Drugs

• Mycobacteria are intrinsically resistant to most
  antibiotics.
• They grow slowly compared with other bacteria,
  antibiotics that are most active against growing
  cells are relatively ineffective. so, thats why
  we use cobination of drugs.
• Mycobacterial cells can also be dormant and thus
  completely resistant to many drugs or killed only
  very slowly.

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Anti Mycobacterial Drugs

• The lipid rich mycobacterial cell wall is
  impermeable to many agents(e.g. drugs).
• Mycobacterial species are intracellular
  pathogens, and organisms residing within
  macrophages are inaccessible to drugs that
  penetrate these cells poorly.
• Finally,mycobacteria are notorius for their
  ability to develop resistance.

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• Combinations of two or more drugs are required to
  overcome these obstacle and to prevent emergence
  of resistance during the course of therapy.
• The response of mycobacterial infections to
  chemotherapy is slow, and treatment must be
  administered for months to years, depending on
  which drugs are used.

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Anti Mycobacterial Drugs

• Drugs Used in Tuberculosis
• First-line drugs
• Rifampin,
• Isoniazid (INH),
• Pyrazinamide,
• Ethambutol, and
• Streptomycin
• These drugs are the first-line agents for
  the treatment of tuberculosis.
• Isoniazid and Rifampin are the two most active
  drugs.

• Mnemonics ? RIPES

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Anti Mycobacterial Drugs

• An isoniazid - rifampin combination administered
  for 9 months will cure 95-98 of cases of
  tuberculosis caused by susceptible strains.
• The addition of pyrazinamide to an isoniazid
  rifampin combination for the first two months
  allow the total duration of therapy to be reduced
  to 6 months without loss of efficacy.

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Anti Mycobacterial Drugs

• In practice therapy is initiated with a four drug
  regimen of isoniazid, rifampin, pyrazinamide, and
  either ethambutol or streptomycin to determine
  susceptibility to the clinical isolate.

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1-ISONIAZID (INH)

• It is a chemo not antibiotic.
• Isoniazid is the most active drug for the
  treatment of tuberculosis caused by susceptible
  strains.
• It is small (MW137) and freely soluble in water.
• It has the structural similarity to pyridoxine
  (Vit.B6)
• It is bactericidal for actively growing tubercle
  bacilli.

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ISONIAZID (INH)

• It is less effective against atypical
  mycobacterial species.
• Isoniazid penetrates into macrophages and is
  active against both extra- and intracellular
  organisms.

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Mechanism of Action and Basis of Resistance
INH, a prodrug
Mycolic acid, essential component of cell wall
KatG enzyme, a mycobacterial catalase peroxidase
enzyme, activates INH
DNA
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• The activated form of isoniazid forms a covalent
  complex with an acyl carrier protein (AcpM) and
  KasA, a ß-ketoacyl carrier protein
  synthetase, which blocks mycolic acid synthesis
  and kills the cell.

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Mechanism of Resistance

• Resistance can emerge rapidly if the drug is used
  alone.
• Resistance can occur due to either
• High-level resistance is associated with deletion
  in the katG gene that codes for a catalase
  peroxidase involved in the bioactivation of INH.
• Low-level resistance occurs via deletions in the
  inhA gene that encodes target enzyme an acyl
  carrier protein reductase.

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PHARMACOKINETICS

• Drug resistant mutants are normally present in
  susceptible mycobacterial populations at about
  1bacillus in 106.
• PHARMACOKINETICS
• Isoniazid is readily absorbed from the
  gastrointestinal tract.
• Dosage 300mg daily per oral or 5mg/kg/d for
  children. Peak plasma concentration 3-5mcg/ml
  achieved within 1-2 hours.

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PHARMACOKINETICS

• Isoniazid diffuses readily into all body fluids
  and tissues.
• The concentration in the CNS and CSF ranges
  between 20 and 100 of simultaneous serum
  concentrations.
• Metabolism of isoniazid, especially acetylation
  by liver N-acetyl transferase, is genetically
  determined.

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Pharmacokinetics of Isoniazid

• The average plasma concentration of isoniazid in
  rapid acetylators is about one third to one half
  of that in slow acetylators, and average half
  lives are less than 1hour and 3 hours,
  respectively.
• More rapid clearance of isoniazid by rapid
  acetylators is usually of no therapeutic
  consequence when appropriate doses are
  administered daily, but subtherapeutic
  concentration may occur if drug is administered
  as a once-weekly dose or if there is malabsorption

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Pharmacokinetics of Isoniazid

• Isoniazid metabolites and a small amount of
  unchanged drug are excreted mainly in the urine.
• The dose need not be adjusted in renal failure.
• Dose adjustment is not well defined in patients
  with severe preexisting hepatic insufficiency
  (isoniazid is contraindicated if it is the cause
  of the hepatitis).

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CLINICAL USES

• 1. Infections caused by mycobacterium
• tuberculosis along with other
• antitubercular drugs
• Dosage 300mg/day per oral adults, or 900mg
  twice/week. 5mg/kg/day in children.
• 2. INH is the primary drug used to treat latent
  tuberculosis, 300mg/day alone
• or 900mg twice/week for 9 months.

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Adverse Reactions of INH

• The incidence and severity of untoward
  reactions related to dosage and duration of
  administration.
• Immunologic reactions

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Adverse Reactions of INH

• 2. Direct toxicity
• Isoniazid induced hepatitis (most common major
  toxic effect). Clinical hepatitis with
• loss of appetite,
• nausea,
• vomiting,
• jaundice and
• right upper quadrant pain, there is histologic
  evidence of hepatocellular damage and necrosis.
  The risk of hepatitis depends on age, rarely
  occurs under age of 20,
• 2.3 for aged 50 and above.

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Adverse Reactions of INH

• The risk of hepatitis is higher in
• alcoholics,
• pregnancy and
• postpartum period.
• 3. Peripheral neuropathy in 10-20 of patients
  given dosages greater than 5mg/kg/day but
  infrequently seen with the standard 300mg adult
  dose.
• It is more likely to occur in slow acetylators
  and patients with malnutrition, alcoholism,
  diabetes and AIDS. Neuropathy is due to relative
  deficiency of pyridoxine.

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Adverse Reactions of INH

• 4. CNS toxicity, which is less common includes
  memory loss, psychosis and seizures. These may
  also respond to pyridoxine.
• 5. Miscellaneous adverse effects
• Provocation of pyridoxine deficiency anemia,
  tinnitus and gastrointestinal discomfort.
• Drug interactions isoniazid can reduce the
  metabolism of phenytoin.

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2-RIFAMPIN

• Rifampin is a semisynthetic derivative of
  rifamycin, an antibiotic produced by Streptomyces
  mediterranei.
• It is active in vitro against gram positive and
  gram negative cocci, some enteric bacteria,
  mycobacteria and chlamydia.

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ANTIMICROBIAL ACTIVITY AND RESISTANCE

• Rifampin binds to the ß subunit of
• bacterial DNAdependent RNA
• polymerase and thereby inhibits
• RNA synthesis.
• Resistance results from any one of
• several possible point mutations in rpoB,
• the gene for the ß subunit of RNA
• polymerase.

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Rifampin

• These mutations result in reduced binding of
  rifampin to RNA polymerase.
• Human RNA polymerase does not bind rifampin and
  is not inhibited by it.
• Rifampin is bactericidal for mycobacteria. It
  readily penetrates most tissues and phagocytic
  cells.

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Rifampin

• It can kill organisms that are poorly accessible
  to many other drugs, such as intracellular
  organisms and those sequestered in abscesses and
  lung cavities.
• Pharmacokinetics
• Rifampin is well absorbed after oral
  administration.

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• It is excreted mainly through the liver into
  bile.
• It then undergoes an enterohepatic circulation,
  with the bulk excreted as a de-acylated
  metabolite in feces and a small amount in the
  urine.
• Rifampin is distributed widely in body fluids
  and tissues.
• Rifampin is relatively highly protein bound and
  adequate CSF concentrations are achieved only in
  the presence of meningeal inflammation.

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CLINICAL USES

• 1. Mycobacterial infections
• Rifampin usually600mg/day, 10mg/kg/day,
• orally must be administered with isoniazid
• or other antituberculous drugs to patients
• with active tuberculosis to prevent emergence of
  drug resistant mycobacteria.

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CLINICAL USES

• 2. Atypical mycobacterial infections.
• 3. Leprosy.
• in these above two conditions rifampin
  600mg daily or twice weekly for 6 months is
  effective in combination with other agents.
• 4. As alternative of isoniazid in prophylaxis
  of latent tuberculosis 600mg/day as a single
  agent for 4 months, in patients with
  isoniazid-resistance or rifampin-susceptible
  bacilli.

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CLINICAL USES

• 5. In exposure to a case of active
• tuberculosis caused by an isoniazid
• resistant, rifampin susceptible strain.
• 6. To eliminate meningococcal
• carriage,600mg, twice daily, for 2 days.
• 7. To eradicate staphylococcal carriage
• with combination to other agent.

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CLINICAL USES

• 8. Osteomyelitis and prosthetic valve
  endocarditis caused by staphylococci in
  combination therapy with other agent.

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• Adverse effects
• 1. Rifampin imparts a harmless orange color to
  urine, sweat, tears and contact lenses.
• 2. Occasional adverse effects

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Drug interactions

• Rifampin strongly induces most cytochrome p450
  isoforms (3A4,2C9,2D6,2C19,1A2).
• Anticoagulants, cyclosporine, anticonvulsants,
  contraceptives, methadone, protease inhibitors,
  non-nucleoside reverse transcriptase inhibitors.
• Administration of rifampin results in
  significantly lower serum levels of these drugs.

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3-Ethambutol

• Ethambutol is a synthetic water soluble, heat
  stable compound, the dextro-isomer of the
  structure dispensed as the dihydrochloride salt.
• Ethambutol inhibits mycobacterial arabinosyl
  transferases. Arabinosyl transferases are
  involved in the polymerization reaction of
  arabinoglycan, an essential component of the
  mycobacterial cell wall.

• Mechanism of action

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• Resistance to ethambutol is due to mutations
  resulting in overexpression of emb gene products
  or within the emb B structural gene.
• Pharmacokinetics
• Ethambutol is well absorbed from the gut.
• After ingestion of 25mg/kg, a blood level peak of
  2-mcg/mL is reached in 2-4 hours.

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Pharmacokinetics

• About 20 drug excreted in feces and 50 in urine
  in unchanged form.
• Ethambutol crosses the blood brain barrier only
  if the meninges are inflammed.
• Ethambutol accumulates in renal failure and the
  dose should be reduced by half if creatinine
  clearance is less than 10mL/min.
• Resistance to ethambutol emerges rapidly when
  used alone, therefore it is always given with
  other antitubercular agents.

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Clinical Uses of Ethambutol

• Tuberculosis
• Ethambutol hydrochloride 15-25mg/kg/d is usually
  given as a single daily dose in combination with
  isoniazid or rifampin.
• Adverse effects
• Retrobulbar (optic) neuritis resulting in loss of
  visual acuity and red green color blindness.
  Usually occur at doses of 25mg/kg/day continued
  for several months.

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Precaution contraindication

• Periodic visual acuity testing is desirable if
  the 25mg/kg/day dosage is used.
• It is relatively contraindicated in children too
  young to permit assessment of visual acuity and
  red green color discrimination.

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4-PYRAZINAMIDE

• Pyrazinamide (PZA) is a relative of
  nicotinamide, stable and slightly soluble in
  water.
• It is inactive at neutral PH, But at PH 5.5 it
  inhibits tubercle bacilli, and some other
  mycobacteria at concentrations of approximately
  20mcg/ml.

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• The drug is taken up by macrophages and exerts
  its activity against mycobacteria residing
  within the acidic environment of lysosomes.
• Pyrazinamide is converted to pyrazinoic acid, the
  active form of the drug, by microbial
  pyrazinamidase, which is encoded by pncA.

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• The drug target and mechanism of action are
  unknown.
• Resistance may be due to impaired uptake of
  pyrazinamide or mutations in pncA that impair
  conversion of pyrazinamide to its active form.

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• Pharmacokinetics
• Pyrazinamide is well absorbed from GIT.
• It is widely distributed in body tissues,
  including inflammed meninges.
• The half life is 8-11 hours.
• The parent compound is metabolized by the liver,
  but metabolites are renally cleared.
• Dosage 25-35 mg/kg/day or 40-50mg/kg
  thrice/week.

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Clinical Uses of Pyrazinamide

• Pyrazinamide is an important front line drug
  used in conjuction with isoniazid rifampin in
  short course (i.e 6 months) regimens as a
  sterilizing agent active against residual
  intracellular organisms that may cause relapse.

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Advese effects of Pyrazinamide

• Hepatotoxicity (in 1-5 of patients-major adverse
  effect).
• Hyperuricaemia (it may provoke acute gouty
  arthritis).
• Nausea, vomiting, drug fever.

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5-STREPTOMYCIN

• Streptomycin was isolated from a strain of
  Streptomyces griseus.
• Mechanism of action
• Like all aminoglycosides, streptomycin
  irreversibly inhibits bacterial protein
  synthesis. Protein synthesis is inhibited in at
  least three ways

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Mechanism of Action of Strept.

• 1. interference with the initiation complex of
  peptide formation.
• 2. Misreading of mRNA, which causes
  incorporation of incorrect aminoacids into the
  peptide, resulting in a nonfunctional or toxic
  protein.
• 3. Breakup of polysomes into nonfunctional
  monosomes.

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Mechanism of resistance

• 1. Production of a transferase enzyme or
  enzymes inactivates the aminoglycosides by
  acetylation, adenylylation or phosphorylation
  (major action).
• 2. Impaired entry of drug into the cell.
• 3. The receptor protein on the 30s ribosomal
  subunit may be deleted or altered as a result of
  mutation.

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Dose kinetics

• Streptomycin penetrates into cells poorly and is
  active mainly against extracellular tubercle
  bacilli.
• Streptomycin crosses the blood brain barrier and
  achieves therapeutic concentrations with inflamed
  meninges.
• Dosage 1g/day or 15mg/kg/day i.m or i.v

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CLINICAL USES

• Tuberculosis
• Streptomycin is used when an injectable drug
  is needed, principally in individuals with
  severe, possibly life threatening forms of
  tuberculosis eg, meningitis and disseminated
  disease.

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Adverse Effects

• Ototoxicity
• Nephrotoxicity
• Toxicity is dose related and the risk is
  increased in elderly

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ALTERNATIVE SECOND-LINE DRUGS FOR TUBERCULOSIS

• The alternative drugs are usually consider
  only
• 1. In case of resistance to first line agents.
• 2. In case of failure of clinical response to
• convential therapy
• 3. In case of serious treatment limiting
• adverse drug reactions
• 4. when expert guidance is available to
• deal with the toxic effects.

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ETHIONAMIDE

• Ethionamide is chemically related to
  isoniazid.
• It is poorly water soluble and available only in
  oral form.
• Mechanism of action
• Ethionamide blocks synthesis of mycolic acids in
  susceptible organisms.

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Pharmacokinetics

• It is metabolized by the liver
• Dosage usual dose, 500 - 750mg/day.
• It is initially given 250mg daily, then increase
  up to 1g/day or 15mg/kg/day.

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• Adverse effects
• Intense gastric irritation
• Neurologic symptoms
• Hepatotoxicity
• Neurologic symptoms may be alleviated by
  pyridoxine.

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CAPREOMYCIN

• Capreomycin is an antibiotic from streptomyces
  capreolus
• Mechanism of action
• It is a peptide protein synthesis inhibitor.
• Capreomycin is an important agent for the
  treatment of drug resistant tuberculosis.
• Strains of M tuberculosis that are resistant to
  streptomycin or amikacin usually susceptible to
  capreomycin

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• Dosage 15mg/kg/day I/M.
• Adverse drug reactions
• Nephrotoxicity
• Ototoxicity tinnitus, deafness, vestibular
  disturbance may occur.
• Local pain sterile abscesses due to injection.

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CYCLOSERINE

• Cycloserine is an antibiotic produced by
  streptomyces orchidaceus.
• Cycloserine is a structural analog of D- alanine.
• Mechanism of action
• It inhibits the incorporation of D- alanine into
  peptidoglycan pentapeptide by inhibiting alanine
  racemase, which converts L-alanine to D- alanine,
  and D- alanyl-D alanine ligase (finally inhibits
  mycobacterial cell wall synthesis).

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• Cycloserine used exclusively to treat
• tuberculosis caused by mycobacterium
  tuberculosis resistant to first line agents
• Dosage o.5 - 1g/day in two or three divided
  doses.

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Adverse effects

• CNS dysfunction, including depression and
  psychotic reactions.
• Peripheral neuropathy.
• Seizures
• Tremors
• Pyridoxine 150mg/day should be given with
  cycloserine because this ameliorates neurologic
  toxicity.

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Aminosalicylic acid (PAS)

• Aminosalicylic acid is a folate synthesis
  antagonist that is active almost exclusively
  against mycobacterium tuberculosis.
• it is structurally similar to p-aminobenzoic
  acid(PABA) and the sulfonamides.

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Pharmacokinetics

• Dosage 4 -12g/day PO (adult)
  300mg/kg/day for children PO
• It is readily absorbed from GIT.
• The drug is widely distributed in tissues and
  body fluids except CSF.

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Pharmacokinetics Adverse effects

• It is readily excreted in the urine, in part as
  active aminosalicylic acid and in part as the
  acetylated compound and other metabolic products.
• Adverse effects
• Peptic ulcer and gastic hemorrhage.
• Hypersensitivity reactions (manifested by fever,
  joint pain, hepatosplenomegaly,hepatitis,granulocy
  topenia, adenopathy) often occur after 3-8 weeks
  of aminosalicylic acid therapy.

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Fluoroquinolones

• Ciprofloxacin, Levofloxacin, gatifloxacin,
  moxifloxacin can inhibit strains M tuberculosis.
• They are also active against atypical
  mycobacteria.
• Moxifloxacin is the most active against M
  tuberculosis.

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• Fluoroquinolones are an important addition to the
  drugs available for tuberculosis, especially for
  strains that are resistant to first line agents.
• Dosage
• Ciprofloxacin 750mg BD,PO
• Levofloxacin 500mg OD.PO
• Moxifloxacin 400mg OD. PO

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Mechanism of action

• They inhibit bacterial DNA synthesis by
  inhibiting bacterial topoisomerase II (DNA
  Gyrase) and topoisomerase IV.
• Inhibition of DNA Gyrase prevents the relaxation
  of positively supercoiled DNA that is required
  for normal transcription and replication.

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MECHANISM OF ACTION

• Inhibition of topoisomerase IV interferes with
  separation of replicated chromosomal DNA into the
  respective daughter cells during cell division.

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Adverse effects

• Nausea,vomiting,diarrhoea(mostcommon).
• Headache, dizziness, insomnia,
• skin rash, photosensitivity.
• Damage growing cartilage and cause an
  arthropathy.
• Tendinitis, tendon rupture.

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Kanamycin Amikacin

• Kanamycin has been used for the treatment of
  tuberculosis caused by streptomycin resistant
  strains, but the availability of less toxic
  alternatives (eg capreomycin and amikacin) has
  renderd it obsolete.

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• Amikacins role in the treatment of tuberculosis
  has increased with the increasing incidence and
  prevalence of multidrug resistant tuberculosis.
• Prevalence of amikacin resistant strains is low
  and most multidrug resistant strains remain
  amikacin susceptible.

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• Amikacin is also active against atypical
  mycobacteria.
• Dosage 15mg/kg IV infusion.
• Clinical uses
• Amikacin is indicated for the treatment of
  tuberculosis suspected or known to be caused by
  streptomycin resistant or multi drug resistant
  strains.

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LINEZOLID

• Linezolid has been used in combination with
  other second and third line drugs to treat
  patients with tuberculosis caused by multi drug
  resistant strains.
• Dosage 600mg/day.
• Linezolid should be considerd a drug of last
  resort for infection caused by multi drug
  resistant strains that are also resistant to
  several other first and second line agents.

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Adverse effects

• Bone marrow depression
• Irreversible peripheral and optic
• neuropathy reported with prolonged use
• of drug

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• RIFABUTIN
• Rifabutin is derived from rifamycin and is
  related to rifampin.
• It has significant activity against mycobacterium
  tuberculosis , M avium- intracellulare and
  mycobacterium fortuitum
• Dosage 300mg/day.

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Clinical uses

• Rifabutin is effective in prevention and
  treatment of disseminated atypical mycobacterial
  infection in AIDS.
• As preventive therapy of tuberculosis.
• It is a hepatic enzyme inducer of cytochrome P450
  enzymes.

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RIFAPENTINE

• Rifapentine is an analog of rifampin.
• It is active against both M tuberculosis and M
  avium
• Mechanism of action
• It is a bacterial RNA polymerase inhibitor.
• Pharmacokinetics
• Rifapentine and its active metabolite, 25
  desacetyl rifapentine have an elimination half
  life of 13 hours.

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RIFAPENTINE

• Clinical uses
• It is indicated for treatment of tuberculosis
  caused by rifampin- susceptible strains during
  the continuation phase only (i.e after the 2
  months of therapy and ideally after conversion
  of sputum cultures to negative).

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LEPROSY

• Leprosy is a chronic infectious disease caused by
  the acid fast rod Mycobacterium leprae.
• The mode of transmission probably is respiratory
  and involves prolonged exposure in childhood.

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LEPROSY

• Symptoms and Signs
• 1. onset is insidious
• 2. Lesions involve the cooler body tissues
• skin, superficial nerves, nose, pharynx,
• larynx, eyes, and testicles.
• 3. skin lesions may occur as pale,
• anesthetic macular lesions 1 10 cm in
• diameter

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LEPROSY

• Discrete erythematous, infiltrated nodules 1- 5
  cm in diameter or a diffuse skin infiltration.
• Neurologic disturbances are manifested by nerve
  infiltration and thickening, with resultant
  anesthesia, neuritis and paraesthesia. Bilateral
  ulnar neuropathy is highly suggestive.

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LEPROSY

• In untreated cases, disfigurement due to the skin
  infiltration and nerve involvement may be
  extreme, leading to trophic ulcers, bone
  resorption, and loss of digits.

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LEPROSY

• Essential of Diagnosis
• Pale, anesthetic macular or nodular and
  erythematous skin lesions.
• Superficial nerve thickening with associated
  anesthesia
• History of residence in endemic area in childhood
• Acid fast bacilli in skin lesions or nasal
  scraping or charact. histologic nerve changes.

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DRUGS USED IN LEPROSY

• 1. DAPSONE OTHER SULFONES
• used effectively in the long-term treatment of
  leprosy.
• Mechanism of action
• Dapsone like the sulfonamides, inhibits folate
  synthesis (PABA antagonist).
• bacteriostatic

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DAPSONE OTHER SULFONES

• Resistance can emerge in large populations of M
  leprae, eg, in lepromatous leprosy, if very low
  doses are given.
• combination of dapsone, rifampin and clofazimine
  is recommended for initial therapy.

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DAPSONE OTHER SULFONES

• Clinical uses
• Leprosy
• Tuberculoid leprosy with rifampin
• Lempromatous leprosy with rifampin and
  clofazimine
• Prevention and treatment of pneumocystis jiroveci
  pneumonia in AIDS patients.
• Pharmacokinetics
• Sulfones are well absorbed from the gut and
  widely distributed throughout body fluids and
  tissues.
• T1/2 1-2 days

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DAPSONE OTHER DRUGS

• Drug tends to be retained in the skin, muscle,
  liver and kidney.
• Skin heavily infected with M leprae may contain
  several times more drug than normal skin.
• Sulfones are excreted into bile reabsorbed in
  the intestine.
• Excretion into urine is variable, and most
  excreted drug is acetylated.
• Adjust dose in renal failure

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DAPSONE OHER SULFONES

• Dosage 100mg daily in leprosy.
• (for children the dose is depending on weight)
• Adverse effects
• Haemolysis ( in patients having G6PD deficiency).
• Methemoglobenemmia
• GI intolerance
• Fever
• Pruritus and various rashes

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DAPSONE OTHER SULFONES

• Erythema nodosum leprosum
• Develops during dapsone therapy of lepromatous
  leprosy.
• Suppressed by corticosteroids or thalidomide

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2.RIFAMPIN

• Rifampin is highly effective in lepromatous
  leprosy.
• Dosage 600mg daily.
• Because of resistant, the drug is given in
  combination with dapsone or another anti leprosy
  drug.
• A single monthly dose of 600mg may be beneficial
  in combination therapy.

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3.CLOFAZIMINE

• Clofazimine is a phenazine dye that can be used
  as an alternative to dapsone.
• Mechanism of action
• Unknown, but may involve DNA binding.
• Clofazimine binds to DNA inhibits template
  function. Its redox properties may lead to
  generation of cytotoxic oxygen radicals that are
  also toxic to the bacteria.
• bactericidal

101
Pharmacokinetics

• Absorption from the gut is variable
• Major portion of the drug is excreted in the
  faeces
• Clofazimine is stored widely in
  reticuloendothelial tissues and skin, and its
  crystal can be seen inside phagocytic
  reticuloendothelial cells.

102
Pharmacokinetics

• It is slowly released from these deposits, so
  that the serum half life may be 2 months.
• Clofazimine is given for sulfone resistant
  leprosy or when patients are intolerent to
  sulfones.
• Dosage 100mg/day

103
Adverse effects

• Skin discoloration ranging from red brown to
  nearly black (major adverse effect)
• Gastrointestinal intolerance occurs
  occasionally.(eosinophilic enteritis)